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The brain is the central and most complex organ in the nervous system, comprising billions of neurons that constantly communicate through trillions of connections called synapses. Despite being formed mainly during prenatal and early postnatal development, synapses are continually refined and eliminated throughout life via complicated and hitherto incompletely understood mechanisms. Failure to correctly regulate the numbers and distribution of synapses has been associated with many neurological and psychiatric disorders, including autism, epilepsy, Alzheimer’s disease and schizophrenia. Therefore, measurements of brain synaptic density, as well as early detection of synaptic dysfunction, are essential for understanding normal and abnormal brain development. To date, multiple synaptic density markers have been proposed and investigated in experimental models of brain disorders. The majority of the gold standard methodologies (e.g. electron microscopy or immunohistochemistry) visualize synapses or measure changes in pre- and postsynaptic proteins ex vivo. However, the invasive nature of these classic methodologies precludes their use in living organisms. The recent development of positron emission tomography (PET) tracers (such as [18F]UCB-H or [11C]UCB-J) that bind to a putative synaptic density marker, the synaptic vesicle 2A (SV2A) protein, is heralding a likely paradigm shift in detecting synaptic alterations in patients. Despite their limited specificity, novel, non-invasive magnetic resonance (MR)-based methods also show promise in inferring synaptic information by linking to glutamate neurotransmission. Although promising, all these methods entail various advantages and limitations that must be addressed before becoming part of routine clinical practice. In this review, we summarize and discuss current ex vivo and in vivo methods of quantifying synaptic density, including an evaluation of their reliability and experimental utility. We conclude with a critical assessment of challenges that need to be overcome before successfully employing synaptic density biomarkers as diagnostic and/or prognostic tools in the study of neurological and neuropsychiatric disorders.

Transcranial magnetic stimulation (TMS) is used in several FDA-approved treatments and, increasingly, to treat neurological disorders in off-label uses. However, the mechanism by which TMS causes physiological change is unclear, as are the origins of response variability in the general population. Ideally, objective in vivo biomarkers could shed light on these unknowns and eventually inform personalized interventions. Continuous theta-burst stimulation (cTBS) is a form of TMS observed to reduce motor evoked potentials (MEPs) for 60 min or longer post-stimulation, although the consistency of this effect and its mechanism continue to be under debate. Here, we use glutamate-weighted chemical exchange saturation transfer (gluCEST) magnetic resonance imaging (MRI) at ultra-high magnetic field (7T) to measure changes in glutamate concentration at the site of cTBS. We find that the gluCEST signal in the ipsilateral hemisphere of the brain generally decreases in response to cTBS, whereas consistent changes were not detected in the contralateral region of interest (ROI) or in subjects receiving sham stimulation.

This study aimed to investigate the diagnostic value of combined glutamate chemical exchange saturation transfer (GluCEST) imaging and γ-aminobutyric acid (GABA)-edited proton magnetic resonance spectroscopy ( 1 H-MRS) in localizing epileptogenic foci and differentiating drug-resistant epilepsy (DR) from drug-responsive epilepsy (DRES) in temporal lobe epilepsy (TLE) using 5T MRI. Twenty-four TLE patients (13 left, 11 right) and 25 age-/gender-matched healthy controls (HCs) underwent GluCEST and MEGA-PRESS MRS at 5T MRI. Directional asymmetry indices (DAIglu_H for hippocampus, DAIglu_A for amygdala) and a novel composite biomarker (DAIglu_GABA) integrating GluCEST asymmetry and GABA/Cr ratios were analyzed. Another asymmetry metric was employed to discriminate the left and right TLE groups [DAIglu_H(epi) for hippocampus, DAIglu_A(epi) for amygdala]. Subgroup comparisons (HC vs. DR vs. DRES) and receiver-operating characteristic (ROC) analyses were performed.

Hippocampal glutamate (Glu) dysfunction is a pertinent indicator of neurodegeneration, yet mapping typical age-related changes in Glu has been challenging. Here, we use a 7T MRI approach, Glutamate Chemical Exchange Saturation Transfer (GluCEST), to measure bilateral hippocampal Glu in healthy old (HOA) and young (HYA) adults. Bilateral hippocampal GluCEST data was acquired from 27 HOA and 22 HYA using 7T MRI. GluCEST differences by age and hemisphere were tested with a linear mixed model. GluCEST asymmetry index was also evaluated by age. Exploratory analyses examined associations between hippocampal GluCEST, age group, and scores on the Montreal Cognitive Assessment (MoCA) and Cognitive Complaints Index (CCI). GluCEST levels showed an age group and hemisphere interaction. In HOA, GluCEST was higher in left than right hippocampus, but in HYA, GluCEST level was equivalent across hemispheres. HOA had lower GluCEST than HYA in the right hippocampus. GluCEST asymmetry index confirmed significant left asymmetry in HOA. Lower GluCEST levels in HOA were associated with subjective cognitive complaints as measured by the CCI. Hippocampal GluCEST provides insight into age-related neural changes, with lower GluCEST in the right hippocampus in older adults. These findings offer a step toward elucidating the asymmetrical trajectory of hippocampal glutamatergic alterations and their relationship to cognitive phenotypes.

Huntington's disease (HD) is an inherited neurodegenerative disease characterized by motor, cognitive and psychiatric symptoms. Atrophy of the striatum has been proposed for several years as a biomarker to assess disease progression in HD gene carriers. However, it does not provide any information about the biological mechanisms linked to HD pathogenesis. Changes in brain metabolites have been also consistently seen in HD patients and animal models using Magnetic Resonance Spectroscopy (MRS), but metabolite measurements are generally limited to a single voxel. In this study, we used Chemical Exchange Saturation Transfer imaging of glutamate (gluCEST) in order to map glutamate distribution in the brain of a knock-in mouse model (Ki140CAG) with a precise anatomical resolution. We demonstrated that both heterozygous and homozygous mice with pathological CAG repeat expansion in gene encoding huntingtin exhibited an atrophy of the striatum and a significant alteration of their metabolic profile in the striatum as compared to wild type littermate controls. The striatal decrease was then confirmed by gluCEST imaging. Surprisingly, CEST imaging also revealed that the corpus callosum was the most affected structure in both genotype groups, suggesting that this structure could be highly vulnerable in HD. We evaluated for the first time gluCEST imaging as a potential biomarker of HD and demonstrated its potential for characterizing metabolic defects in neurodegenerative diseases in specific regions. [Display omitted] •A knock-in mouse model of Huntington's disease Ki140CAG is characterized.•Behavioral tests, MRS and glutamate imaging reveal significant alterations in mice.•The glutamate distribution is mapped in vivo into the brain using gluCEST imaging.•GluCEST imaging is proposed as a potential biomarker of Huntington's disease.

•Glutamate, a critical amino acid for the brain, can be detected by gluCEST imaging.•Whole brain gluCEST maps were recorded at high field (11.7T) MRI in a primate.•Regional differences of gluCEST contrast strongly reflect glutamate pathways.•gluCEST imaging highlights regional age-related alterations.•gluCEST imaging highlights age-related alterations in large-scale networks. Glutamate is the amino acid with the highest cerebral concentration. It plays a central role in brain metabolism. It is also the principal excitatory neurotransmitter in the brain and is involved in multiple cognitive functions. Alterations of the glutamatergic system may contribute to the pathophysiology of many neurological disorders. For example, changes of glutamate availability are reported in rodents and humans during Alzheimer's and Huntington's diseases, epilepsy as well as during aging. Most studies evaluating cerebral glutamate have used invasive or spectroscopy approaches focusing on specific brain areas. Chemical Exchange Saturation Transfer imaging of glutamate (gluCEST) is a recently developed imaging technique that can be used to study relative changes in glutamate distribution in the entire brain with higher sensitivity and at higher resolution than previous techniques. It thus has strong potential clinical applications to assess glutamate changes in the brain. High field is a key condition to perform gluCEST images with a meaningful signal to noise ratio. Thus, even if some studies started to evaluate gluCEST in humans, most studies focused on rodent models that can be imaged at high magnetic field. In particular, systematic characterization of gluCEST contrast distribution throughout the whole brain has never been performed in humans or non-human primates. Here, we characterized for the first time the distribution of the gluCEST contrast in the whole brain and in large-scale networks of mouse lemur primates at 11.7 Tesla. Because of its small size, this primate can be imaged in high magnetic field systems. It is widely studied as a model of cerebral aging or Alzheimer's disease. We observed high gluCEST contrast in cerebral regions such as the nucleus accumbens, septum, basal forebrain, cortical areas 24 and 25. Age-related alterations of this biomarker were detected in the nucleus accumbens, septum, basal forebrain, globus pallidus, hypophysis, cortical areas 24, 21, 6 and in olfactory bulbs. An age-related gluCEST contrast decrease was also detected in specific neuronal networks, such as fronto-temporal and evaluative limbic networks. These results outline regional differences of gluCEST contrast and strengthen its potential to provide new biomarkers of cerebral function in primates. [Display omitted]

Purpose Glutamate chemical exchange saturation transfer (GluCEST) is a non-invasive CEST imaging technique for detecting glutamate levels in tissues. We aimed to investigate the reproducibility of the 5T GluCEST technique in healthy volunteers and preliminarily explore its potential clinical application in patients with brain tumors. Methods Ten volunteers (4 males, mean age 29 years) underwent three 5T GluCEST imaging scans. The reproducibility of the three imaging GluCEST measurements was assessed using one-way repeated measures analysis of variance (ANOVA), generalized estimating equations, and linear mixed models. Twenty-eight patients with brain tumors (10 males, mean age 54 years) underwent a single GluCEST scan preoperatively, and t-tests were used to compare the differences in GluCEST values between different brain tumors. In addition, the diagnostic accuracy of GluCEST values in differentiating brain tumors was assessed using the receiver work characteristics (ROC) curve. Results The coefficients of variation of GluCEST values in healthy volunteers were less than 5% for intra-day, inter-day, and within-subjects and less than 10% for between-subjects. High-grade gliomas (HGG) had higher GluCEST values compared to low-grade gliomas (LGG) ( P  < 0.001). In addition, cerebellopontine angle (CPA) meningiomas had higher GluCEST values than acoustic neuromas ( P  < 0.001). The area under the curve (AUC) of the GluCEST value for differentiating CPA meningioma from acoustic neuroma was 0.93. Conclusion 5T GluCEST images are highly reproducible in healthy brains. In addition, the 5T GluCEST technique has potential clinical applications in differentiating LGG from HGG and CPA meningiomas from acoustic neuromas.

INTRODUCTION Regional glucose hypometabolism resulting in glutamate loss has been shown as one of the characteristics of Alzheimer's disease (AD). Because the impact of AD varies between the sexes, we utilized glutamate‐weighted chemical exchange saturation transfer (GluCEST) magnetic resonance imaging (MRI) for high‐resolution spatial mapping of cerebral glutamate and investigated subregional changes in a sex‐specific manner. METHODS Eight‐month‐old male and female AD mice harboring mutant amyloid precursor protein (APPNL‐F/NL‐F: n = 36) and wild‐type (WT: n = 39) mice underwent GluCEST MRI, followed by proton magnetic resonance spectroscopy (1H‐MRS) in hippocampus and thalamus/hypothalamus using 9.4T preclinical MR scanner. RESULTS GluCEST measurements revealed significant (p ≤ 0.02) glutamate loss in the entorhinal cortex (% change ± standard error: 8.73 ± 2.12%), hippocampus (11.29 ± 2.41%), and hippocampal fimbriae (19.15 ± 2.95%) of male AD mice. A similar loss of hippocampal glutamate in male AD mice (11.22 ± 2.33%; p = 0.01) was also observed in 1H‐MRS. DISCUSSIONS GluCEST MRI detected glutamate reductions in the fimbria and entorhinal cortex of male AD mice, which was not reported previously. Resilience in female AD mice against these changes indicates an intact status of cerebral energy metabolism. Highlights Glutamate levels were monitored in different brain regions of early‐stage Alzheimer's disease (AD) and wild‐type male and female mice using glutamate‐weighted chemical exchange saturation transfer (GluCEST) magnetic resonance imaging (MRI). Male AD mice exhibited significant glutamate loss in the hippocampus, entorhinal cortex, and the fimbriae of the hippocampus. Interestingly, female AD mice did not have any glutamate loss in any brain region and should be investigated further to find the probable cause. These findings demonstrate previously unreported sex‐specific glutamate changes in hippocampal sub‐regions using high‐resolution GluCEST MRI.

Background Hyperinsulinism hyperammonemia (HI/HA) syndrome is caused by activating mutations in GLUD1 , encoding glutamate dehydrogenase (GDH). Atypical absence seizures and neuropsychological disorders occur at high rates in this form of hyperinsulinism. Dysregulated central nervous system (CNS) glutamate balance, due to GDH overactivity in the brain, has been hypothesized to play a role. This study aimed to describe the neurologic phenotype in HI/HA syndrome and investigate CNS glutamate levels using glutamate weighted chemical exchange saturation transfer magnetic resonance imaging (GluCEST MRI). In this cross-sectional study, 12 subjects with HI/HA syndrome had plasma ammonia measurement, self- or parent-completed neurocognitive assessments, electroencephalogram (EEG), and GluCEST MRI at 7 T performed. GluCEST MRI measures were compared to a historic reference population of 10 healthy adults. Results Subjects were five males and seven females with median age of 25.5 years. Seventy-five percent of subjects reported a history of neurodevelopmental problems and 42% had neurocognitive assessment scores outside the normal range. Fifty percent had interictal EEG findings of generalized, irregular spike and wave discharges. Higher variability in hippocampal GluCEST asymmetry ( p  = 0.002), and in peak hippocampal GluCEST values ( p  = 0.008), was observed in HI/HA subjects (n = 9 with interpretable MRI) compared to the healthy reference population (n = 10). Conclusions The high prevalence of abnormal neurocognitive assessment scores and interictal EEG findings observed highlights the importance of longitudinal neuropsychological assessment for individuals with HI/HA syndrome. Our findings demonstrate the potential application of GluCEST to investigate persistent knowledge gaps in the mechanisms underlying the unique neurophenotype of this disorder.

Objective: Malformations of cortical development (MCDs) are major causes of intractable epilepsies. To characterize the early neuroimaging findings of MCDs, we tried to identify the MRI features consistent with pathological findings in an infant rat MCD model, prenatally exposed to methylazoxymethanol (MAM), by using newly developed MRI techniques. Methods: At gestational day 15, two doses of MAM (15 mg/kg intraperitoneally) or normal saline were injected into pregnant rats. The offspring underwent in vivo MRI, including glutamate chemical exchange saturation transfer (GluCEST), 1H-MR spectroscopy, and diffusion tensor imaging, at postnatal day (P) 15 using a 7T small-animal imaging system. Another set of prenatally MAM-exposed rats were sacrificed for histological staining. Results: At P15, the retrosplenial cortex (RSC) of rats with MCDs showed decreased neuronal nuclei, parvalbumin, and reelin expressions. Moreover, dendritic arborization of pyramidal cells in the RSC significantly decreased in infant rats with MCDs. In vivo MRI showed significantly decreased GluCEST (%) in the RSC of rats with MCDs (p < 0.001) and a significant correlation between GluCEST (%) and RSC thickness (r = 0.685, p = 0.003). The rats with MCDs showed reduced glutamate (p = 0.002), N-acetylaspartate (p = 0.002), and macromolecule and lipid levels (p < 0.05) and significantly reduced fractional anisotropy values in the RSC. Conclusions: In vivo MRI revealed reduced neuronal population and dendritic arborization in the RSC of infant rats with MCDs during the early postnatal period. These pathological changes of the cortex could serve as clinical imaging biomarkers of MCDs in infants.